ABSTRACT Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by myelin damage in the brain and spinal cord. The current diagnosis and management of MS rely primarily on magnetic resonance imaging (MRI), which provides a means to detect overall changes in tissue water content. However, lesions detected by MRI reflect only macroscopic tissue injuries that are not necessarily caused by myelin damage. Consequently, the use of MRI as a primary measure of disease activity is poorly correlated with clinical outcomes in MS. This long-standing clinico-radiological paradox in MS is considered as a missing link to finding a cure for MS as it hampers efficacy evaluation of putative MS therapies, particularly myelin-repair therapies that are designed to promote long-term functional restoration. To overcome this challenge, we hypothesize that positron emission tomography (PET) imaging, when used in combination with myelin-specific radiotracers, will be able to directly detect and quantify changes of myelin distribution in the brain and spinal cord and that measurement will correlate with clinical evaluation. To test this hypothesis, we have developed a series of myelin-imaging agents that readily penetrate the blood-brain barrier and selectively localize in the brain and spinal cord in proportion to the myelin content. In preliminary studies, we identified a lead radioligand, termed [11C]MeDAS, that is specific for PET imaging of myelin changes and suitable for translational studies. In order to implement [11C]MeDAS-PET in a clinical setting, we plan to address the following specific aims: 1) Characterization of the binding properties of MeDAS in the postmortem human brain and spinal cord tissues; 2) Conduct [11C]MeDAS- PET imaging in non-human primates; and 3) Conduct Phase I/II studies in human subjects to evaluate safety and provide initial proof-of-concept data for measurement of myelin content. Successful completion of these studies will validate [11C]MeDAS-PET as a unique imaging marker for unambiguous monitoring of disease progression or recession and myelin-repair processes in MS. !